Here is the paper that shows a significant decrease in Ruminoccus in Norwegian patients. It does not seem to mention a decrease in Bifidobacteria or in overall diversity, but I believe these are both fairly common findings in his patients (when I was tested, I had almost no Bifidobacteria).

Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

The paper does mention ruminococcus, but mentions lots of other things as well in those results; one would have to look at all the detail to determine to what extent the rest of his findings are consistent with what Hanson found.

I do not believe he has published the findings about LPS anywhere, but he mentions it in this video at 6.00:

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It's been observed a few times before that it's a shame that KDM doesn't seem to publish papers regarding a lot of the things he talks about. If he did, that would be the way to get more people following up on what he says. But no doubt funding is a major issue there.

According to KDM, the level of LPS in the plasma correlates with the severity of the disease, so it will be interesting to see if Hanson confirms this finding.

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It certainly will! At IiME it did seem like they were very interested in LPS; if one of these candidates could be shown to be correlated with severity or specific symptoms or subsets, I think that would be very significant.

KDM also says that the severely ill patients had higher levels of LPS than did AIDS patients in a 2006 study.

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A reference for that study would be helpful too.

The good news is, he may have found one of the causes of this, described in a meeting abstract that was recently posted in the ME - current research forum.

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Another reference you might like to track down...

I really think we would be a lot further ahead by now if there had been a group (preferably with more money than KDM) that had just dedicated itself to confirming KDM´s findings, along with those of Maes.

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Hindsight is a wonderful thing. There have been so many promising leads and so many dead ends; so much that should have been properly followed up, and would have been followed up if the proper funding had been there. I've felt for a long time that when the answers finally come, we will look back and see that some of the key features were actually found 20 years ago or more and not followed up. Further on from that, when it's all well understood, we'll be able to see a simple test or piece of research that could have resolved things decades ago if only we'd known exactly what to do. But I think that's all hindsight really. It's always easier to work out the answer when you already know what the answer is! The problem is sifting through all the findings and figuring out which ones are true, which aren't, and which are significant and why. Having weak evidence of something is one thing; having proof is quite another - and all the necessary studies cost money. And a lot of what has been published will turn out to be flat out wrong - likely that will be the case for much or most of the published biomedical research on ME/CFS too - perhaps also for much or most of what KDM himself has published or claimed. Still, I do agree that all these things should have been properly followed up.

Oh, and in the same video KDM coins a new name for the disease: Gut-Immune-Neurotoxic Disease, which isn´t a million miles away from your description above.

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Yes, that's very similar, but that aspect isn't surprising. I think this model of causality is fairly well established now in a number of diseases; perhaps a quarter or half of the IiME presenters over the last few years have been talking along similar lines, and talking about that as an established model for other diseases as they've done so...at least, if I've understood things correctly...

NB. In the video, he actually mentions an increase in Bifidobacteria in patients, along with a decrease in the gram-negative to gram-positive ratio, but this was based on culture tests, not on the 16S rRNA tests he now uses, which I believe show the opposite in both these cases.

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As I say. Another confounder is the mechanisms mentioned (by Scheibenbogen) whereby different pairs of antibodies (that either up-regulate or down-regulate their targets) could cause opposite symptoms in individuals who have one or the other, or both opposing sets of symptoms in patients that have both! There are lots of bits and pieces here, but it's fairly likely the picture will get even more complex in the next few years...

Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

The paper does mention ruminococcus, but mentions lots of other things as well in those results; one would have to look at all the detail to determine to what extent the rest of his findings are consistent with what Hanson found.

It's been observed a few times before that it's a shame that KDM doesn't seem to publish papers regarding a lot of the things he talks about. If he did, that would be the way to get more people following up on what he says. But no doubt funding is a major issue there.

It certainly will! At IiME it did seem like they were very interested in LPS; if one of these candidates could be shown to be correlated with severity or specific symptoms or subsets, I think that would be very significant.

A reference for that study would be helpful too.

Another reference you might like to track down...

Hindsight is a wonderful thing. There have been so many promising leads and so many dead ends; so much that should have been properly followed up, and would have been followed up if the proper funding had been there. I've felt for a long time that when the answers finally come, we will look back and see that some of the key features were actually found 20 years ago or more and not followed up. Further on from that, when it's all well understood, we'll be able to see a simple test or piece of research that could have resolved things decades ago if only we'd known exactly what to do. But I think that's all hindsight really. It's always easier to work out the answer when you already know what the answer is! The problem is sifting through all the findings and figuring out which ones are true, which aren't, and which are significant and why. Having weak evidence of something is one thing; having proof is quite another - and all the necessary studies cost money. And a lot of what has been published will turn out to be flat out wrong - likely that will be the case for much or most of the published biomedical research on ME/CFS too - perhaps also for much or most of what KDM himself has published or claimed. Still, I do agree that all these things should have been properly followed up.

Yes, that's very similar, but that aspect isn't surprising. I think this model of causality is fairly well established now in a number of diseases; perhaps a quarter or half of the IiME presenters over the last few years have been talking along similar lines, and talking about that as an established model for other diseases as they've done so...at least, if I've understood things correctly...

As I say. Another confounder is the mechanisms mentioned (by Scheibenbogen) whereby different pairs of antibodies (that either up-regulate or down-regulate their targets) could cause opposite symptoms in individuals who have one or the other, or both opposing sets of symptoms in patients that have both! There are lots of bits and pieces here, but it's fairly likely the picture will get even more complex in the next few years...

I think the surprising thing is that the video is six years old - I am not aware of anyone else describing the disease in those terms in 2010 (except perhaps Maes). I agree that it would have been better if KDM had published more, but like you said, money was probably a limiting factor.

I do not believe that ´much of what KDM has claimed may turn out to be false´, but it may not be the whole picture. In my view the disease is at least partially driven by the gut issues, but it may also be driven by autoimmunity in some patients - or perhaps there is some autoimmunity going on that affects the gut? I think the key to it all is working out why Ritux works for some, but I guess that isn´t all that easy to do...

This is an excellent artice, @Mark! Thanks so much to you and @Kina to attending the conference on behalf of all of us who can't go. I know what an immense amount of work it must have been to have produced something this comprehensive in so short a space of time and it's hugely appreciated - the suspense is terrible for those of us waiting for the DVD!

Especially exciting to hear in some detail about Ron Davis's work. If you're planning more detailed versions of each presentation, I hope you might start with his!

This is an excellent artice, @Mark! Thanks so much to you and @Kina to attending the conference on behalf of all of us who can't go. I know what an immense amount of work it must have been to have produced something this comprehensive in so short a space of time and it's hugely appreciated - the suspense is terrible for those of us waiting for the DVD!

Especially exciting to hear in some detail about Ron Davis's work. If you're planning more detailed versions of each presentation, I hope you might start with his!

Really terrific job.

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Thanks Sasha. Yes it's a lot of work, but I do enjoy it and it helps me get a lot more out of the conference and understand it better.

MEAction did a great article about Ron Davis' talk, and I wrote an extended section on that presentation including everything in my notes that wasn't covered in their piece. So I'm not planning on adding anything further about that one - sorry. I'll have another look but I think it's pretty much been covered now.

>Here is the paper that shows a significant decrease in Ruminoccus in Norwegian patients. It does not seem to mention a decrease in Bifidobacteria or in overall diversity, but I believe these are both fairly common findings in his patients (when I was tested, I had almost no Bifidobacteria).

Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

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This study only had 43 mecfs patients and 36 heathy controls, which is very small. But that'st the total sample, the nationality groups are even smaller. I don't think you can read anything into this, especially as the biggest difference they found was between healthy Norwegians and equally healthy Belgians, which could be down to diet and mean nothing (though it's likely to be an unreliable finding given such a small sample).

Maybe one day there will be enough data for someone to do a meta-analysis, combinging data from many small studies to look for an overall effect. Though of course nationality (and diet) will confound that, making it harder to do.

EMERG and EUROMENE have met together to clarify their different roles: EMERG will focus on infrastructure and establishing a European research agenda; EUROMENE will establish networks of researchers and stakeholders.

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I suspect I'm not the only one a bit confused by this - it seems odd for one group to establish a European research agenda that the other is presumably expected to buy in to. Hopefully stuff like this will work itself out in time

At UCL they have been investigating phenotype sub-populations of naive and memory B cells in ME/CFS patients. Cambridge introduced Ph.D. student Fane Mensah who has been working on this.

Mensah presented a preliminary conclusion that they believe they have confirmed dysregulation of B cells associated with the CD24 marker in ME/CFS patients. He explained that they are now investigating interactions between B cells and T-cells in patients, using an in vitro system to explore soluble serum factors, and looking at mitochondrial mass, proliferation, CD23 differentiation and antibody production.

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Cool! That seem to be upping the game in the sophistication of looking at immune cell function. (I think the NIH intramural study will do this too, one of those study leader Nath mentions is an expert at studying immune cell interactions, eg the B/T cell interaction that Mensah is studying)

Also, this seems a good place to park the official IiME abstract ofJo Cambridge's talk, where she gives what I thought was a really helpful explanation of how and why rituximab works in general.

… B cells are produced in the bone marrow, pass into the tissues, recognise antigens, following which they can interact with T cells, develop into plasma cells which then secrete antibodies.

B cells are killed by rituximab, which binds the CD20 molecule on B cells. It is used immunotherapeutically in rheumatoid arthritis, lupus and lymphoma, all of which are affected by B cell function. Rituximab does not affect pre-B cells or plasma cells.

In the clinic, rituximab (2 x 1 gm) is given intravenously 1-2 weeks apart. B cells are quickly killed in the blood, but decline slowly in the tissues. A blood test is performed at one month to see if the B cells are decreased, but there may be residual memory cells left in the lymphoid organs. B cells start to resume exit from the bone marrow at approximately 6 months.

Rituximab works best in autoimmune diseases where auto-antibodies are part of the disease process. It removes the “parent” B cells of the rapidly turning over (short-lived) plasmablasts which make the auto-antibodies, and therefore stops the supply of auto-antibodies to tissues or from making part of pro-inflammatory immune complexes (such as in lupus and rheumatoid arthritis).

Because of some positive outcomes in ME/CFS, does this imply that auto-antibodies are part of the disease process?

The clinical response to rituximab can take months, and the time varies between diseases and patients. Tests need to be done at baseline, depletion stage, repopulation stage and during relapse. The B cells return once the rituximab is cleared from the bone marrow. Relapse is not always associated with B cell return. In rheumatoid arthritis, 70% respond to rituximab and, B cells are back in approximately 6 months. Some B cells can trigger a relapse when they come back but this is not always the case.

In ME/CFS, rituximab may therefore stop the B cells differentiating into plasma cells, and stops the B cells interacting with other cells (such as T cells). Treatment protocols should thus be fitted to how the B cells are involved, by looking at the changes in the B cells. Interventions should be modelled specifically in the immune system changes in ME/CFS in order to target the patients most likely to respond.
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Hi Mark, great job! I'm still working my way through as I've not been too well and have lots of questions, but as you tagged me, here's a response for now:
This study only had 43 mecfs patients and 36 heathy controls, which is very small. But that'st the total sample, the nationality groups are even smaller. I don't think you can read anything into this, especially as the biggest difference they found was between healthy Norwegians and equally healthy Belgians, which could be down to diet and mean nothing (though it's likely to be an unreliable finding given such a small sample).

Maybe one day there will be enough data for someone to do a meta-analysis, combinging data from many small studies to look for an overall effect. Though of course nationality (and diet) will confound that, making it harder to do.

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Yes, it´s a small study, but then so are almost all of the studies done on ME so far. I don´t understand statistics, but doesn´t the fact that the same differences/trends were found between patients and controls in both the Belgian and Norwegian groups count for something? I think statisticians and medical types sometimes overlook what I would call circumstantial evidence.

Also, going back to my original point, surely if it´s worth mentioning the findngs of the small Hanson study then its worth mentioning that it replicates the findings of an earlier small study?

Yeah, they need to watch out or it will be all over Pirate Bay and YouTube.

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I guess I'll be buying a DVD player then. I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

"The DVD's are heavily subsidised in order to make them available to as many patients, patient groups, carers and researchers, healthcare, media and politicians."

I guess I'll be buying a DVD player then. I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

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Could they monetize streaming ? I presume one of their aims is not to loose money either.

I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

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I think it might simply be a case of being a bit old fashioned, and trusting what you know.

Oddly enough, I have several computers, none of which have a DVD drive. These days you can get by without one.

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Yes, DVDs are a bit old fashioned these days. I wish they'd place the videos on Vimeo, or similar. The production costs would be cheaper too. But it's just a minor grumble. The DVDs are an amazing resource. I've watched every conference since they began.